The incidence of pancreatic carcinoma has increased dramatically over the past three decades, currently ranking as the fourth leading cause of cancer mortality in the United States. Delineating molecules that contribute to pancreatic cancer initiation and/or progression should lead to a better understanding of the biology of this devastating disease, while potentially providing novel therapeutic targets or prognostic indicators. We have identified the nonreceptor tyrosine kinase pp72syk as a molecule aberrantly expressed in a subset of pancreatic adenocarcinoma cells. Expression of syk in these cells correlates with loss of the tumor suppressor DPC4, and with the presence of detergent-soluble E-cadherin, which is lost by the DPC4- positive, syk-negative cells. Thus, syk may define a potential pathway of pancreatic tumor progression in cells that express functional E-cadherin. Indeed, these protein expression profiles may define alternate mechanisms of tumor progression that direct distinct patterns of tumor dissemination. Syk-positive pancreatic tumor cells display pronounced local invasion in the absence of distant metastasis in an orthotopic animal model of pancreatic cancer, similar to the unresectable clinical presentation of roughly 25% of human patients. In contrast, syk-negative pancreatic tumor cells exhibit extensive dissemination to distant organs in the absence of significant local invasion in the same animal model. Syk is not detectable in normal pancreatic epithelial cells of the adult pancreas, however we have observed syk expression in malignant ducts of archival clinical specimens. Therefore, we propose to investigate the potential role of syk in the biology of pancreatic adenocarcinoma by both assessing the phenotype of recombinantly engineered cells in an orthotopic animal model, and by examining syk expression and activation state in archival specimens. These studies should validate syk as a player in the biology of pancreatic adenocarcinoma, and should provide the basis for further investigations into the role of this kinase in this devastating disease.